PD10-05 PHASE 3 STUDY OF INTERMITTENT MONOTHERAPY VERSUSCONTINUOUS COMBINED ANDROGEN DEPRIVATION

1 1 2 3 4 5 6 7Calais da Silva Junior F. , Calais da Silva Senior F. , Gonçalves F. , Kliment J. , Santos A. , Pastidis S. , Queimadelos A. , Robertson C. 1 2 3 4 CHLC ‐ Hospital de São José, Dept. of Urology, Lisboa, Portugal, CUIMED A Saint Michal Hospital, Dept. of Urology, Bratislava, Slovakia, Jessenius Schooll of Medicine, Dept. of Urology, Martin, Slovakia, Hospital de Braga, Dept. of Urology, Braga, Portugal, 5 6 7 Amalia Fleming Hospital, Dept. of Urology, Athens, Greece, Policlinica La Rosaleda, Dept. of Urology, Santiago Compostela, Spain, University of Stracthclyde, Dept. of Urology, Glasgow, United Kingdom

CONCLUSIONS

Follow up has been extended to a maximum of 17 years and 13% of patients are still in active follow up. We are at the 658 deaths specified in the protocol and there is no evidence that an initial treatment with intermittent therapy is harmful to patients in that overall survival is poorer and we can conclude that intermittent therapy is equivalent to continuous in terms of overall survival. There are no differences in cause specific hazards of death though there is a slight tendency to have slightly poorer survival on continuous therapy driven largely by elevated cardio vascular deaths over the whole follow up period but particularly up to 10 years following randomization. There is no difference in prostate cancer deaths, though those randomized to intermittent therapy have a higher hazard of a death due to a non‐prostate cancer.

RESULTS

1045 men with a median PSA of 15.9ng/ml were registered between October 1999 and September 2007. 24.5% of registered patients have a PSA less than 10ng/ml; 39.5% of registered patients have a PSA greater than 20ng/ml. 90.3% have a T3 tumour and 5.6% T4; only 14% have metastatic prostate cancer, 63% have Gleason Score 6‐7 and 21% Gleason 8+. 918 patients (aged 44‐81, mean 72) have been randomized 462 to Intermittent therapy and 456 to Continuous. The median PSA is 1.0 ng/ml ranging from 0.1 to 9. 49.2% of patients have a PSA less than 1 ng/ml at randomisation.

The maximum follow up is 17.2 years with a median of 5.8 years. 214 patients were still alive more than 10 years following randomization, 107 on Intermittent therapy and 107 on Continuous, representing 23% of patients randomized.

A total of 658 (331 Intermittent, 327 Continuous) patients have died; 208 from prostate cancer (106 Intermittent and 102 Continuous), 275 from CVD (131 Intermittent and 144 Continuous), 46 from other metastatic disease (29 Intermittent and 17 Continuous) 129 from Other Causes, including unknown cause (65 Intermittent and 64 Continuous).

Median survival is 6.5 years (95% CI 6.0, 6.9) and 536 patients have been followed up for at least five years, with 363 for at least 7 years and 117 for at least 12 years (13% of those randomized to intermittent therapy and 13% of those on continuous). Metastatic status, PSA and age at randomization are all prognostic factors for survival. M1 patients have an increased risk of dying (HR=1.64, 95% CI 1.28, 2.09) and there is a trend for an increasing hazard of death with increasing age so that men aged 75+ have a hazard ratio of 1.79 (95% CI 1.21, 2.66) compared to men aged under 60. Men whose PSA falls to between 2 and 4 have an increased hazard of dying relative to those whose PSA falls below 0.5 (HR=1.86, 95% CI 1.52, 2.27). Adjusting for Age, metastatic status and PSA, there was no evidence that T Stage (p=0.82) or Gleason score (p=0.20) are associated with an increased risk of death.

Adjusting for Age, PSA and metastatic status, patients on intermittent therapy had a reduced hazard of death compared to continuous therapy, HR= 0.92 (95% CI 0.79, 1.06), p = 0.27, Figure 1. The hazard of a CVD death is HR=0.84 (95% CI 0.66, 1.06, p = 0.15), Figure 2, while for other metastatic disease it is HR = 1.56 (95% CI 0.86, 2.86, p = 0.14), Figure 3. For Prostate cancer HR = 0.96 (95% CI 0.73, 1.27 , p = 0.77), Figure 4, and for other causes of death it is HR = 0.89 (95% CI 0.63, 1.27 , p = 0.52), Figure 5.

INTRODUCTION AND OBJECTIVE

Intermittent androgen deprivation therapy can only be appropriately evaluated in a randomized fashion. We present updated follow up results, to Sept 2017, from the SEUG 9901 Phase III study comparing the intermittent monotherapy with continuous combined androgen deprivation using an LHRH analogue and ciproterone acetate and associated components of quality of life. The study was powered to establish equivalence of mortality in intermittent therapy compared to continuous. Assuming a HR = 1.21 for Intermittent compared to continuous, then based on a one‐sided logrank test for equivalence at error rates alpha = 0.05 and beta = 0.20, a total of 658 deaths were required. This total has now been reached.

BEST PATIENT

Based on results from SEUG 9401 and 9901, we can define an optimal candidate for intermittent therapy as: (1) M0; (2) T3 (3) PSA levels prior to induction therapy <100 ng/ml, and whose PSA decreases to < 4 ng/ml (preferably <1 ng/ml) after 3 months of induction therapy. Intermittent therapy is less likely to be beneficial for patients with metastasis and bone hot spots, with high initial PSA levels (>100 ng/ml), severe pain or extensive disease.The main reason that the latter group do not benefit from intermittent therapy is that they tend to go on to continuous therapy relatively quickly.

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OVERALL SURVIVAL

Figure 1. Survival curves, in months from randomization, for OverallSurvival by Continuous Therapy (Red) and Intermittent Therapy (Black).

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CARDIO VASCULAR DISEASE

Figure 2. Survival curves, in months from randomization, for time to death from CVD by Continuous Therapy (Red) and Intermittent Therapy (Black). Deaths from other cause are censored.

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OTHER METASTATIC DISEASE

Figure 3. Survival curves, in months from randomization, for time to death from cancer, excluding, prostate cancer by Continuous Therapy (Red) and Intermittent Therapy (Black). Deaths from other cause are censored.

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PROSTATE CANCER

Figure 4. Survival curves, in months from randomization, for time to death from Prostate Cancer by Continuous Therapy (Red) and Intermittent Therapy (Black). Deaths from other cause are censored.

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OTHER CAUSES OF DEATH

Figure 5. Survival curves, in months from randomization, for time to death from all causes of death other than (CVD, and cancer, by Continuous Therapy (Red) and Intermittent Therapy (Black). Deaths from other cause are censored.